Inflammation is a big deal in the medical world. Even mild inflammation, if it’s consistently present, is known to increase one’s risk of getting cardiovascular diseases, diabetes, Alzheimer’s and many others. Standard tests for inflammation such as C-reactive protein or cholesterol, however, are often unrevealing. For instance, inflammation is a key driver of heart disease, but the first sign for many of heart problems is still a heart attack.

Chronic, low levels of inflammation are found in many serious diseases.

Likewise it’s been said that chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM) are inflammatory diseases, but standard tests for inflammation often indicate that none is present. Dr. Montoya believes that current inflammation tests are missing a lot and that future tests will be able to detect the kind of inflammation occurring in ME/CFS.

Given that tests for inflammation are relatively crude, it makes sense that significant efforts would be directed to developing a better test. It’s no surprise that Mark Davis at Stanford is involved.

A 2015 study overturned decades of perceived wisdom that self-attacking or auto-reactive lymphocytes are mostly weeded out early in childhood. (They’re actually very common in adults.) Davis upended another pillar of orthodoxy when he determined that environment – the microbes, toxins, foods, etc. that we encounter – have far more of an impact on our immune system than our genes. Davis found, for instance, that a single cytomegalovirus infection causes stunningly large and permanent changes to our immune systems.

Davis is bold enough to want to replace all mouse research forever (“Free the mice!”) with a human based approach using immune modeling. In 2015 the Bill Gates foundation gave him $50 million to figure out how to build more effective vaccines. Lastly and most importantly for us, Davis is one of the luminaries sitting on the Open Medicine Foundation’s Scientific Board. A friend of Ron Davis, I met him at the Davis’ Palo Alto fundraiser a year or so ago. (He said when Ron Davis asks you to do something, you do it).

Davis may have come up with the best test yet for inflammation – an apt subject for ME/CFS and FM patients. In fact this test sounds like it was made for people with chronic fatigue syndrome and fibromyalgia.

Old Before Their Time?

The study originated in an attempt to quantify the link between inflammation and something perhaps pertinent to chronic fatigue syndrome and fibromyalgia – aging. While the evidence is sketchy, it does suggest that people with ME/CFS and/or FM might be aging faster. Decreased brain gray matter, shortened telomere lengths, gait alterations, and the cognitive and sleep issues, could all reflect a group of patients who are aging a bit before their time.

In this study researchers studied two groups of 40 individuals, one between 40 and 60 years old and one over the age of 60, for nine years. Every year they threw a battery of specialized immune tests at them, and at the end of the study assessed their cardiovascular health by measuring levels of atherosclerotic plaque, arterial stiffness and ventricular function.

Their goal – to develop a better immune test that can predict cardiovascular risk due to inflammation much earlier than is currently possible.

“Wired and Tired” Immune Systems Spark Inflammation

They hit the jackpot when they measured immune cells responsiveness to cytokines. Younger study participants demonstrated a quick and dramatic response to the cytokines- their T-cells went into a tizzy, but the older participants produced a more muted response.

Tired immune systems may be sparking inflammation

We usually think of immune activation as potentially bad – as a driver of inflammation, and so it is at times. This study suggests, though, that the kind of immune activation present is the key.

The older persons’ immune systems were, in fact, overly activated – but not in response to the cytokines. They were hyped up before the cytokine test; i.e. they were mildly activated (“wired and tired”?) all the time. When presented with a stressor, though, the immune cells pooped out.

If that pattern sounds familiar, it should. ME/CFS/FM patients appear to have activated sympathetic nervous systems at rest which also poop out when they’re put under strain. ME/CFS/FM patients low heart rate variability (HRV) scores also demonstrate a less responsive system is present.

A cytokine responsiveness score (composed of 15 different cytokine responsiveness tests) indicated that the always-on-but-muted immune response to danger was not good news. It was associated with signs of atherosclerosis and the inability of the heart to relax between beats.

This study suggests that it’s not the big burst of immune activity that is perilous for most of us. A nice, sharp increase in immune responsiveness is actually a sign of health. It’s the always on, lower levels of immune activation that cause the inflammation that results in so much trouble for so many people – and perhaps in ME/CFS.

It suggests the system doesn’t have to be fully activated to create inflammation; it simply has to be exhausted. The reduced blood and spinal fluid cytokine levels Lipkin and Hornig found in ME/CFS smacked of immune exhaustion. The Columbia-Simmaron Research spinal fluid studies that published those results continue in an effort to characterize the neurological levels of inflammation and immune response and move us closer to treatments.

Several studies suggest that increased oxidative stress and vascular characteristics of people with chronic fatigue syndrome may put them at increased risk of cardiovascular issues. Improperly functioning mitochondria can produce massive amounts of free radicals and thus inflammation, which in turn furthers hampers mitochondrial functioning.

A Mitochondrial Immune Connection?

Any discussion of “exhaustion” has to touch on the mitochondria. It turns out that immune exhaustion may very well be linked to mitochondrial problems.

Early on Ron Davis suggested that energy problems in ME/CFS could be affecting the immune cells in particular. Immune cells typically don’t use a lot of energy until they come upon a pathogen, at which point they use enormous amounts of energy to transform themselves into fighting machines that attack the defender and pump out scads of cytokines. If mitochondrial dysfunction is present it might very well show up in the immune cells in spades.

Armstrong and McGregor’s metabolomic findings suggested that ME/CFS patients were in energy depleted states similar to those found in inflammatory, sepsis-like conditions or starvation. Their work suggested that energy depletion (immune exhaustion?) may be associated with inflammation in ME/CFS.

Naviaux believes the mitochondria provide our first and perhaps most precise reflection of immune health. His insights into the mitochondria/immune interface has guided much of his work.

The Stanford immune responsiveness test is not available yet. Too expensive for clinical use, researchers are trying to find ways to lower its cost. When the Stanford test becomes available it might not be surprising to find ME/CFS and FM patients scoring very low.

In the meantime ME/CFS researchers are avidly exploring the intersection between the immune system and the mitochondria.